(1) Field of the Invention
The present invention generally relates to treatments of demyelinating conditions. More specifically, the invention relates to the use of calcium channel blockers for treating demyelinating conditions, especially multiple sclerosis.
(2) Description of the Related Art
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PCT patent publication WO 92/07564.
Demyelination is a feature of many neurologic disorders. Demyelinating conditions are manifested in loss of myelin—the multiple dense layers of lipids and protein which cover many nerve fibers. These layers are provided by oligodendroglia in the central nervous system (CNS), and Schwann cells in the peripheral nervous system. In patients with demyelinating conditions, demyelination may be irreversible; it is usually accompanied or followed by axonal degeneration, and often by cellular degeneration. Demyelination can occur as a result of neuronal damage or damage to the myelin itself—whether due to aberrant immune responses, local injury, ischemia, metabolic disorders, toxic agents, or viral infections (Prineas and McDonald, 1997; Beers and Berkow, 1999).
Central demyelination (demyelination of the CNS) occurs in several conditions, often of uncertain etiology, that have come to be known as the primary demyelinating diseases. Of these, multiple sclerosis is the most prevalent. Other primary demyelinating diseases include adrenoleukodystrophy, adrenomyeloneuropathy, AIDS-vacuolar myelopathy, HTLV-associated myelopathy, Leber's hereditary optic atrophy, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, and tropical spastic paraparesis. In addition, there are acute conditions in which demyclination can occur in the CNS, e.g., acute disseminated encephalomyelitis and acute viral encephalitis. Furthermore, acute transverse myelitis, a syndrome in which an acute spinal cord transection of unknown cause affects both gray and white matter in one or more adjacent thoracic segments, can also result in demyelination. Finally, there are animal models which mimic features of human demyelinating diseases (Beers and Berkow, 1999). Examples include experimental autoimmune neuritis, demyelination induced by Theiler's virus, and experimental autoimmune encephalomyelitis (EAE)—an autoimmune disease which is experimentally induced in a variety of species and which resembles multiple sclerosis in its clinical and neuropathological aspects (Gold et al., 2000; Njenga and Rodriguez, 1996).
Multiple sclerosis (MS) is the most prevalent demyclinating condition. In Europe and North America, an average of 40-100 people out of every 100,000 have MS. The disease affects approximately 250,000 people in the United States alone. MS is a chronic, devastating neurological disease that affects mostly young adults. The pathogenesis of MS is a complex process that leads to destruction of myelin and oligodendroglia, as well as axonal damage, in the brain and spinal cord (Prineas and McDonald, 1997; Trapp et al., 1998). Histopathologically, MS is characterized by inflammation, plaques of demyelination infiltrating cells in the CNS tissue, loss of oligodendroglia, and focal axonal injury (Prineas and McDonald, 1997). The disease is thought to result from aberrant immune responses to myelin, and possibly non-myelin, self-antigens (Bar-Or et al., 1999; Hartung, 1995). Clinically, MS may follow a relapsing-remitting, or it may take a chronically progressive course with increasing physical disability (Gold et al., 2000). Typically, the symptoms of MS include lack of co-ordination, paresthesias, speech and visual disturbances, and weakness (Beers and Berkow, 1999).
Current treatments for the various demyelinating conditions are often expensive, symptomatic, and only partially effective, and may cause undesirable secondary effects. Corticosteroids (oral prednisone at 60-100 mg/day, tapered over 2-3 weeks, or intravenous methylprednisolone at 500-1000 mg/day, for 3-5 days) represent the main form of therapy for MS. While these may shorten the symptomatic period during attacks, they may not affect eventual long-term disability. Long-term corticosteroid treatment is rarely justified, and can cause numerous medical complications, including osteoporosis, ulcers, and diabetes (Id.).
Immunomodulatory therapy with recombinant human interferon-β (Betaseron and Avonex) and with co-polymer (Copaxon) slightly reduces the frequency of relapses in MS, and may help delay eventual disability (Id.). Both forms of interferon-β and co-polymer are currently used as treatment modalities for MS, but all are exceedingly expensive. Immunosuppressive drugs (azathioprine, cladribine, cyclophosphamide, and methotrexate) are used for more severe progressive forms. However, they are not uniformly beneficial, and have significant toxic side-effects. Several drugs (e.g., baclofen at 30-60 mg/day in divided doses) may reduce spasticity by inhibiting the spinal cord reflexes. Cautious and judicious use is required, though, because the drug-induced reduction in spasticity in MS patients often exacerbates weakness, thereby further incapacitating the patient (Id.).
Similarly, current treatment for adrenoleukodystrophy, another devastating demyelinating disease, is relatively ineffective. Symptoms of adrenoleukodystrophy may include cortical blindness, corticospinal tract dysfunction, mental deterioration, and spasticity. Therapy to control the course of adrenoleukodystrophy may include bone marrow transplantation and dietary treatment (DiBiase et al., 1999), but inexorable neurological deterioration invariably occurs, ultimately leading to death (Krivit et al., 1999). Some progress has been realized in the treatment of animals with EAE and experimental autoimmune neuritis, by using glial cell transplants and growth factors, and by inhibiting adhesion molecules, autoantibodies, and cytokines (Njenga and Rodriguez, 1996). However, none of these treatments has been shown to be beneficial in humans, and some require extensive neurosurgical intervention. Thus, it is clear from the foregoing that there exists a need for more effective, and less expensive and invasive, methods to treat the varied array of demyelinating conditions, without producing undesirable secondary effects.
Calcium-channel blockers are a class of pharmacological agents which inhibit the transmembrane flux of calcium (Ca2+) ions into cells, particularly vascular smooth muscle cells and cardiac muscle cells. They have been indicated for the treatment of angina, arrhythmias, atrial fibrillation, hypertension, and paroxysmal supraventricular tachycardia (Physicians' Desk Reference, 2000). Amlodipine, a potent Ca2+-channel blocker, is a long-acting dihydropyridine calcium antagonist (calcium ion antagonist or slow-channel blocker). Amlodipine selectively inhibits Ca2+-ion influx across cell membranes, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. In particular, amlodipine is a peripheral arterial vasodilator that acts directly on vascular smooth muscle to cause a reduction in peripheral vascular resistance and a reduction in blood pressure. Amlodipine has been demonstrated to be effective in treating chronic stable angina, vasospastic angina, and hypertension (Id.), and it may also have neuroprotective activity (Mason et al., 1999). Other Ca2+-channel blockers include bepridil, nitrendipine, diltiazem, felodipine, flunarizine, isradipine, mibefradil, nicardipine, nifedipine, nimodipine, nisoldipine, nivaldipine, and verapamil (Physicians' Desk Reference, 2000).
There has been a previous suggestion that calcium-channel blockers could be effective for demyelinating conditions. PCT patent publication WO 92/07564, to the Wellcome foundation (“Wellcome”), claims such a use, particularly using nimodipine. However, the skilled artisan would not consider Wellcome to be an enabling disclosure because the cell culture experiment disclosed therein would not be understood to establish the effectiveness of calcium-channel blockers for demyelinating conditions, especially inflammatory demyelinating conditions such as MS.